Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patients With Irritable Bowel Syndrome:
Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of LOTRONEX twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received LOTRONEX and occurred more frequently on LOTRONEX than on placebo. A statistically significant difference was observed for constipation in patients treated with LOTRONEX compared to placebo (p<0.0001).

Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with LOTRONEX [see Warnings and Precautions ]. In clinical studies constipation was reported in approximately 29% of patients with IBS treated with LOTRONEX 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<0.0001). Eleven percent (11%) of patients treated with LOTRONEX 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with LOTRONEX 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with LOTRONEX 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in postmarketing experience [see Boxed Warning and Warnings and Precautions]. In Studies 1 and 2, 9% of patients treated with LOTRONEX reported constipation and 4 consecutive days with no bowel movement [see Clinical Studies ]. Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with LOTRONEX.

Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving LOTRONEX or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving LOTRONEX was reported in a 12-week study. A causal association with LOTRONEX has not been established.

Long-Term Safety: Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months.

Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome:
Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received LOTRONEX and occurred more frequently with LOTRONEX than with placebo. Other events reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches, and fatigue.

Table 2. Gastrointestinal Adverse Reactions Reported in ≥3% of Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome and More Frequently on LOTRONEX Than Placebo.

LOTRONEX

LOTRONEX

LOTRONEX

Adverse Reaction

Placebo

0.5 mg once daily

1 mg once daily

1 mg twice daily

(n = 176)

(n = 175)

(n = 172)

(n = 176)

Constipation

5%

9%

16%

19%

Abdominal pain

3%

5%

6%

7%

Diarrhea

2%

3%

2%

2%

Hemorrhoidal hemorrhage

2%

3%

2%

2%

Flatulence

2%

2%

1%

3%

Hemorrhoids

2%

1%

1%

3%

Abdominal pain upper

1%

3%

1%

1%

Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included constipation (14% and 10% of patients taking LOTRONEX 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting, and flatulence. Other events reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis, and cough.

Constipation: Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2. There was a dose response in the groups treated with LOTRONEX in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily, and 11% on 1 mg twice daily). Among these patients with severe diarrhea-predominant IBS treated with LOTRONEX who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days.

Other Events Observed During Clinical Evaluation of LOTRONEX: During its assessment in clinical trials, multiple and single doses of LOTRONEX were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to LOTRONEX varied between trials, and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications.

In the listing that follows, reported adverse reactions were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to LOTRONEX, occurred in at least 2 patients, and occurred at a greater frequency during treatment with LOTRONEX than during placebo administration are presented. Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with LOTRONEX and occurring at a greater frequency in patients treated with LOTRONEX than placebo-treated patients are also presented.

In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency. The following definitions are used: infrequent adverse reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients.

Although the events reported occurred during treatment with LOTRONEX, they were not necessarily caused by it.

Postmarketing Experience

In addition to events reported in clinical trials, the following events have been identified during use of LOTRONEX in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to LOTRONEX.